Safety monitoring of the RTS,S vaccine pilot implementation programme
GACVS has followed the development and safety evaluation of RTS,S for the past 8 years. A positive scientific opinion of RTS,S has been issued by the European Medicines Agency under Article 58,3 and in January 2016, WHO recommended further evaluation of the vaccine. WHO’s position is based on advice from the Strategic Advisory Group of Experts (SAGE) on Immunization and the Malaria Policy Advisory Committee (MPAC). A series of pilot implementation programmes has been proposed to address several gaps in knowledge before considering introduction of the vaccine at wider country level. These gaps include the extent to which the protection demonstrated in children in the Phase III4 trial, carried out by the manufacturer GlaxoSmithKline (GSK), can be replicated in the context of routine health systems, particularly in view of the need for a 4-dose schedule that requires additional immunization visits; to assess if there is an impact on all-cause mortality, and whether the excess number of cases of meningitis and cerebral malaria identified during the Phase III trial are causally related to RTS,S/AS01 vaccination.5
Ghana, Kenya and Malawi are the 3 pilot implementation countries. Pilot programmes will be conducted in selected areas of moderate to high malaria transmission. Introduction of the vaccine will be through the national Expanded Programmes on Immunization (EPI) in each country, with some districts/counties randomized to receive the vaccine at the beginning of the programme, while others will not begin using the vaccine, allowing comparison of the impact and safety outcomes of interest. Within each country, regulatory approval for pilot introduction will be required prior to vaccine use. GACVS received updates on the draft design of the pilot programmes from WHO, the risk management plan from GSK, the state of routine vaccine pharmacovigilance from experts in the pilot countries, the proposed safety data flow, and the proposal to set up a Programme Safety Committee.
GACVS noted the substantial and continuing disease burden of malaria and the potential impact of the vaccine. The safety of RTS,S will be monitored both through a strengthened routine pharmacovigilance system operating across the entire pilot implementation programme area, and by a specific surveillance system established in sentinel hospitals covering part of the area. The meningitis and cerebral malaria signals previously identified6will be specifically evaluated through systematic, prospective, quality-assured paediatric inpatient surveillance at 8 sentinel hospitals in each country (4 in clusters receiving RTS,S and 4 in control clusters) which will also enable identification and evaluation of other potential safety signals. In addition, the manufacturer will be conducting a Phase IV study in 4 additional hospitals in each country. The Phase IV study, in contrast to the pilot implementation studies, will include follow-up of individuals using a cohort study design. Across the entire pilot area, safety monitoring will include spontaneous reporting of adverse events following immunization (AEFIs) as well as active surveillance (detection, investigation and ascertainment of immunization status of all cases in the corresponding age group detected by the health-care system) for adverse events of special interest (AESIs). While both Ghana and Kenya are members of the WHO programme for international drug monitoring,7Malawi is currently an associate member. GACVS recommended that Malawi receives support to become a full member of the WHO programme.
To strengthen routine pharmacovigilance ahead of the pilot introduction, GACVS recommended that countries be supported with training and logistics. The Committee also discussed criteria for pharmacovigilance readiness. The criteria retained included: a minimum level of 10 annual AEFI reports per 100 000 surviving infants in pilot areas; functional AEFI committees that meet regularly; trained and resourced AEFI investigation teams; safety communication plans to be evaluated and tested; and each country to have an identified person in post within the EPI programme to oversee AEFI reporting and training, and ensure that they are, and remain, optimal. Each pilot country has also consulted, or will be consulting, experts to identify which AESI would be of interest and could practically be assessed by active surveillance. These are events that have been observed with the use of other vaccines, or that reflect theoretical concerns with RTS,S use. GACVS recommended that the list be of a practical size and be the same for all countries with agreed case definitions and procedures for investigation. These AESIs should be assessed as part of the pilot programme with monitoring starting prior to RTS,S introduction to establish a baseline and will be limited to the duration of the pilot programme. Regarding spontaneous AEFI reporting, active AESI surveillance should be in place 6 months prior to the first vaccine administration, also to establish baselines.
In addition, GACVS recommended between-country co-ordination to ensure comparability of AEFI data, and the standardization of causality assessment tools and training materials, including material used within the pilot programmes and by GSK’s Phase IV programme. GACVS agreed that the establishment of a Programme Safety Committee, with membership from pilot and other countries, would enhance this coordination. This Committee would provide an overall evaluation of RTS,S safety and advise on pharmacovigilance capacity in pilot countries; it would also provide GACVS with updates from the pilot programme and prepare the report that would summarize safety data at completion. In the longer term the Programme Safety Committee could be transformed to become a vaccine safety committee for the WHO African Region.
GACVS also reviewed the proposed flow of safety data and recommended that the secretariat of the Malaria Vaccine Implementation Programme maintain a joint dataset of AEFI for review by the Programme Safety Committee. GACVS acknowledged the need for each country to be regularly informed about progress with safety monitoring in other pilot sites including information exchange between each country and the manufacturer. This will be essential to ensure proper information about safety monitoring during Phase IV studies as well as to meet the regulatory requirements of the risk management plan. A pharmacovigilance plan will be prepared jointly with the 3 pilot countries.
As an expert committee, GACVS will continue to provide advice and support to the pilot countries and to the planned Programme Safety Committee. Specifically, it will assist with the interpretation and communication of safety questions and maintain a subcommittee with which the Programme Safety Committee can communicate. A current, or former, GACVS member will also be nominated to ensure proper liaison with the Programme Safety Committee. At its meeting in December 2017, GACVS will review progress with pharmacovigilance readiness ahead of the start of the pilot programmes and provide further advice on the way forward.
3 See http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000157.jsp
4 RTS,S Clinical Trials Partnership. Effi cacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. The Lancet. 2015;386(9988):31–45.
5 See No. 4, 2016, pp. 33–52.
6 See No. 3, 2016, pp. 24–26.
7 See http://www.who.int/medicines/areas/quality_safety/safety_efficacy/National_PV_Centres_Map/en/